Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso.

In this study, we investigated how different categories of prenatal malaria exposure (PME) influence levels of maternal antibodies in cord blood samples and the subsequent risk of malaria in early childhood in a birth cohort study (N = 661) nested within the COSMIC clinical trial (NCT01941264) in Burkina Faso. Plasmodium falciparum infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. The levels of maternal IgG and IgG1-4 to 15 P. falciparum antigens were measured in cord blood by quantitative suspension array technology. Results showed a significant variation in the magnitude of maternal antibody levels in cord blood, depending on the PME category, with past placental malaria (PM) more frequently associated with significant increases of IgG and/or subclass levels across three groups of antigens defined as pre-erythrocytic, erythrocytic, and markers of PM, as compared to those from the cord of non-exposed control infants. High levels of antibodies to certain erythrocytic antigens (i.e., IgG to EBA140 and EBA175, IgG1 to EBA175 and MSP142, and IgG3 to EBA140 and MSP5) were independent predictors of protection from clinical malaria during the first year of life. By contrast, high levels of IgG, IgG1, and IgG2 to the VAR2CSA DBL1-2 and IgG4 to DBL3-4 were significantly associated with an increased risk of clinical malaria. These findings indicate that PME categories have different effects on the levels of maternal-derived antibodies to malaria antigens in children at birth, and this might drive heterogeneity to clinical malaria susceptibility in early childhood.

Effects of maternal antenatal treatment with two doses of azithromycin added to monthly sulfadoxine-pyrimethamine for the prevention of low birth weight in Burkina Faso: an open-label randomized controlled trial.

BACKGROUND: Exposure during pregnancy to malaria and sexually-transmitted infections is associated with adverse birth outcomes including low birth weight (LBW). This study aimed at assessing if the adjunction of two doses of azithromycin to sulfadoxine-pyrimethamine for the intermittent preventive treatment of malaria in pregnancy can reduce LBW. METHODS: A two parallel-groups, open-label randomized controlled trial involving pregnant women (16 to 35 years of age and 12 to 24 weeks of gestation as confirmed by last menstrual period or fundal height) was conducted in rural Burkina Faso. Women were assigned in a 1:1 ratio either to use azithromycin (1 g daily for 2 days) during the second and third trimesters of pregnancy plus monthly sulfadoxine-pyrimethamine (1500/75 mg) (SPAZ) (intervention) or to continue using a monthly sulfadoxine-pyrimethamine (1500/75 mg) (SP) (control). Primary outcome was a LBW (birth weight measured within 24 h after birth < 2500 g). Secondary outcomes including stillbirth, preterm birth or miscarriage are reported together with safety data. RESULTS: A total of 992 pregnant women underwent randomization (496 per group) and 898 (90.5%) valid birth weights were available (450 in SPAZ and 448 in SP). LBW incidence was 8.7% (39/450) in SPAZ and 9.4% (42/448) in controls (p-value = 0.79). Compared with controls, pregnant women with SPAZ showed a risk ratio (RR) of 1.16 (95% confidence interval (CI 0.64-2.08]) for preterm births, 0.75 (95% CI 0.17-3.35) for miscarriage and 0.64 (95% CI 0.25-1.64) for stillbirths. No treatment-related serious adverse events (SAEs) have been observed, and there was no significant difference in the number of SAEs (13.5% [67/496] in SPAZ, 16.7% [83/496] in SP, p-value = 0.18) or AEs (17.1% [85/496] in SPAZ, 18.8% [93/496] in SP, p-value = 0.56). CONCLUSION: Adequate prevention regimen with monthly sulfadoxine-pyrimethamine given to all pregnant women has been proved to reduce the risk of LBW in malaria endemic areas. Adding azithromycin to the regimen does not offer further benefits, as far as women receive a malaria prevention regimen early enough during pregnancy. Trial registration Pan African Clinical Trial Registry ( https://pactr.samrc.ac.za/Search.aspx ): PACTR201808177464681. Registered 21 August 2018.

Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.

BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 µg R21 plus 25 µg MM, group 2 received 5 µg R21 plus 50 µg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Age-modified factors associated with placental malaria in rural Burkina Faso.

BACKGROUND: Malaria in pregnancy can result in placental infection with fetal implications. This study aimed at assessing placental malaria (PM) prevalence and its associated factors in a cohort of pregnant women with peripheral malaria and their offspring. METHOD: The data were collected in the framework of a clinical trial on treatments for malaria in pregnant women . Placental malaria (PM) was diagnosed by histopathological detection of parasites and/or malaria pigment on placenta biopsies taken at delivery. Factors associated with PM were assessed using logistic regression. RESULTS: Out of 745 biopsies examined, PM was diagnosed in 86.8 % of women. Acute, chronic and past PM were retrieved in 11 (1.5 %), 170 (22.8 %), and 466 (62.6 %) women, respectively. A modifying effect was observed in the association of gravidity or anemia at the study start with pooled PM (presence of parasites and/or malaria pigment). In women under 30, gravidity ≤ 2 was associated with an increased prevalence of pooled PM but in women aged 30 years or more, gravidity was no more associated with pooled PM (OR 6.81, 95 % CI 3.18 - 14.60; and OR 0.52, 95 % CI 0.10 - 2.76, respectively). Anemia was associated with pooled PM in women under 30 (OR 1.96, 95 % CI 1.03 - 3.72) but not in women aged 30 years or more (OR 0.68, 95 % CI 0.31 - 1.49). Similarly, the association of gravidity with past-chronic PM depended also on age. A higher prevalence of active PM was observed in women under 30 presenting with symptomatic malaria (OR 3.79, 95 % CI 1.55 - 9.27), while there was no significant increase in the prevalence of active PM (presence of parasites only) in women with symptomatic malaria when aged 30 years or more (OR 0.42, 95 % CI 0.10 - 1.75). In women with chronic PM, the prevalence of low birth weight or prematurity was the highest (31.2 %) as compared with past PM or no PM. CONCLUSION: Despite the rapid diagnosis and efficacious treatment of peripheral infection, the prevalence of placental malaria remained high in women with P. falciparum peripheral infection in Nanoro, especially in younger women This underlines the importance of preventive measures in this specific group.

Low birth weight and its associated risk factors in a rural health district of Burkina Faso: a cross sectional study.

BACKGROUND: Low birth weight (LBW) is a major factor of neonate mortality that particularly affects developing countries. However, the scarcity of data to support decision making to reduce LBW occurrence is a major obstacle in sub-Saharan Africa. The aim of this research was to determine the prevalence and associated factors of LBW at the Yako health district in a rural area of Burkina Faso. METHODS: A cross sectional survey was conducted at four peripheral health centers among mothers and their newly delivered babies. The mothers' socio-demographic and obstetrical characteristics were collected by face-to-face interview or by review of antenatal care books. Maternal malaria was tested by standard microscopy and neonates' birth weights were documented. Multivariate logistic regression was used to determine factors associated with LBW. A p-value < 0.05 was considered statistically significant. RESULTS: Of 600 neonates examined, the prevalence of low birth weight was 11.0%. Adjustment for socio-demographic characteristic, medical conditions, obstetrical history, malaria prevention measures by multivariate logistic regression found that being a primigravid mother (aOR = 1.8, [95% CI: 1.1-3.0]), the presence of malaria infection (aOR = 1.9, [95% CI: 1.1-3.5]), the uptake of less than three doses of sulfadoxine-pyrimethamine for the intermittent preventive treatment of malaria in pregnancy (IPTp-SP) (aOR = 2.2, [95% CI: 1.3-3.9]), the presence of maternal fever at the time of delivery (aOR = 2.8, [95% CI: 1.5-5.3]) and being a female neonate (aOR = 1.9, [95% CI: 1.1-3.3]) were independently associated with an increased risk of LBW occurrence. The number of antenatal visits performed by the mother during her pregnancy did not provide any direct protection for low birth weight. CONCLUSION: The prevalence of LBW remained high in the study area. Maternal malaria, fever and low uptake of sulfadoxine-pyrimethamine doses were significantly associated with LBW and should be adequately addressed by public health interventions.

Plasmodium falciparum gametocyte carriage in symptomatic patients shows significant association with genetically diverse infections, anaemia, and asexual stage density.

BACKGROUND: Multi-genotype malaria infections are frequent in endemic area, and people commonly harbour several genetically distinct Plasmodium falciparum variants. The influence of genetic multiplicity and whether some specific genetic variants are more or less likely to invest into gametocyte production is not clearly understood. This study explored host and parasite-related risk factors for gametocyte carriage, and the extent to which some specific P. falciparum genetic variants are associated with gametocyte carriage. METHODS: Gametocytes and asexual forms were detected by light microscopy on thick smears collected between 2010 and 2012 in Nanoro, Burkina Faso. Merozoite surface protein 1 and 2 were genotyped by nested PCR on clinical samples. Associations between gametocyte carriage and factors, including multiplicity of infection, parasite density, patient age, gender, haemoglobin (Hb) level, and body temperature were assessed. The relationship between the presence of a particular msp1 and msp2 genetic variants and gametocyte carriage was also explored. RESULTS: Of the 724 samples positive to P. falciparum and successfully genotyped, gametocytes were found in 48 samples (6.63%). There was no effect of patient gender, age and body temperature on gametocyte carriage. However, the probability of gametocyte carriage significantly increased with increasing values of multiplicity of infection (MOI). Furthermore, there was a negative association between parasite density and gametocyte carriage. MOI decreased with parasite density in gametocyte-negative patients, but increased in gametocyte carriers. The probability of gametocyte carriage decreased with Hb level. Finally, the genetic composition of the infection influenced gametocyte carriage. In particular, the presence of RO33 increased the odds of developing gametocytes by 2 while the other allelic families K1, MAD20, FC27, and 3D7 had no significant impact on the occurrence of gametocytes in infected patients. CONCLUSION: This study provides insight into potential factors influencing gametocyte production in symptomatic patients. The findings contribute to enhance understanding of risk factors associated with gametocyte carriage in humans. Trial registration NCT01232530.

Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018.

BACKGROUND: The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy. METHODS: This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed. RESULTS: Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64-83%) in Nanoro, 76% (66-83%) in Gourcy, and 92% (84-96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75-89%) in Gourcy, 89% (81-94%) in Nanoro, and 97% (92-99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation. CONCLUSION: The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx.

Genetic variation in the immune system and malaria susceptibility in infants: a nested case-control study in Nanoro, Burkina Faso.

BACKGROUND: Genetic polymorphisms in the human immune system modulate susceptibility to malaria. However, there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who present differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. This study investigated the association between genetic variation in innate immune response genes and malaria susceptibility during the first year of life in 656 infants from a birth cohort survey performed in Nanoro, Burkina Faso. METHODS: Seventeen single nucleotide polymorphisms (SNPs) in 11 genes of the immune system previously associated with different malaria phenotypes were genotyped using TaqMan allelic hybridization assays in a Fluidigm platform. Plasmodium falciparum infection and clinical disease were documented by active and passive case detection. Case-control association analyses for both alleles and genotypes were carried out using univariate and multivariate logistic regression. For cytokines showing significant SNP associations in multivariate analyses, cord blood supernatant concentrations were measured by quantitative suspension array technology (Luminex). RESULTS: Genetic variants in IL-1ß (rs1143634) and FcγRIIA/CD32 (rs1801274)-both in allelic, dominant and co-dominant models-were significantly associated with protection from both P. falciparum infection and clinical malaria. Furthermore, heterozygote individuals with rs1801274 SNP in FcγRIIA/CD32 showed higher IL-1RA levels compared to wild-type homozygotes (P = 0.024), a cytokine whose production is promoted by the binding of IgG immune complexes to Fcγ receptors on effector immune cells. CONCLUSIONS: These findings indicate that genetic polymorphisms in genes driving innate immune responses are associated to malaria susceptibility during the first year of life, possibly by modulating production of inflammatory mediators.

Association of malaria and curable sexually transmitted infections with pregnancy outcomes in rural Burkina Faso.

BACKGROUND: Malaria and curable sexually transmitted infections (STIs) are severe infections associated with poor pregnancy outcomes in sub-Saharan countries. These infections are responsible for low birth weight, preterm birth, and miscarriage. In Burkina Faso, many interventions recommended by the World Health Organization were implemented to control the impact of these infections. After decades of intervention, we assessed the impact of these infections on pregnancy outcomes in rural setting of Burkina Faso. METHODS: Antenatal care and delivery data of pregnant women attending health facilities in 2016 and 2017 were collected in two rural districts namely Nanoro and Yako, in Burkina Faso. Regression models with likelihood ratio test were used to assess the association between infections and pregnancy outcomes. RESULTS: During the two years, 31639 pregnant women received antenatal care. Malaria without STI, STI without malaria, and their coinfections were reported for 7359 (23.3%), 881 (2.8 %), and 388 (1.2%) women, respectively. Low birth weight, miscarriage, and stillbirth were observed in 2754 (10.5 %), 547 (2.0 %), and 373 (1.3 %) women, respectively. Our data did not show an association between low birth weight and malaria [Adjusted OR: 0.91 (0.78 - 1.07)], STIs [Adjusted OR: 0.74 (0.51 - 1.07)] and coinfection [Adjusted OR: 1.15 (0.75 - 1.78)]. Low birth weight was strongly associated with primigravidae [Adjusted OR: 3.53 (3.12 - 4.00)]. Both miscarriage and stillbirth were associated with malaria [Adjusted OR: 1.31 (1.07 - 1.59)], curable STI [Adjusted OR: 1.65 (1.06 - 2.59)], and coinfection [Adjusted OR: 2.00 (1.13 - 3.52)]. CONCLUSION: Poor pregnancy outcomes remained frequent in rural Burkina Faso. Malaria, curable STIs, and their coinfections were associated with both miscarriage and stillbirth in rural Burkina. More effort should be done to reduce the proportion of pregnancies lost associated with these curable infections by targeting interventions in primigravidae women.

Patterns of child mortality in rural area of Burkina Faso: evidence from the Nanoro health and demographic surveillance system (HDSS).

BACKGROUND: Half of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but patterns and potential drivers of heterogeneity in child mortality in the district had not been studied. Similar studies in other districts indicated proximity to health facilities as a risk factor, usually without distinction between facility types. METHODS: Using Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and proximity to inpatient and outpatient health facilities, seasonality of death, age group, and standard demographic risk factors. RESULTS: Living in homes 40-60 min and > 60 min travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13-2.06) and 1.74 (95% CI: 1.27-2.40) greater hazard of under-5 mortality, respectively, than living in homes < 20 min from an inpatient facility. No such association was found for outpatient facilities. The wet season (July-November) was associated with 1.28 (95% CI: 1.07, 1.53) higher under-5 mortality than the dry season (December-June), likely reflecting the malaria season. CONCLUSIONS: Our results emphasize the importance of geographical proximity to health care, distinguish between inpatient and outpatient facilities, and also show a seasonal effect, probably driven by malaria.

Pooled Multicenter Analysis of Cardiovascular Safety and Population Pharmacokinetic Properties of Piperaquine in African Patients with Uncomplicated Falciparum Malaria.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456 ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.).

The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data.

BACKGROUND: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. METHODS: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. RESULTS: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. CONCLUSION: Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. METHODS: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013. RESULTS: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001). CONCLUSIONS: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

In vivo/ex vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso.

BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso. METHODS: In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42. RESULTS: Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05). CONCLUSION: These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1.

First trimester use of artemisinin-based combination therapy and the risk of low birth weight and small for gestational age.

BACKGROUND: While there is increasing evidence on the safety of artemisinin-based combination therapy (ACT) for the case management of malaria in early pregnancy, little is known about the association between exposure to ACT during the first trimester and the effect on fetal growth. METHODS: Data were analysed from prospective studies of pregnant women enrolled in Mozambique, Burkina Faso and Kenya designed to determine the association between anti-malarial drug exposure in the first trimester and pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA). Exposure to anti-malarial drugs was ascertained retrospectively by record linkage using a combination of data collected from antenatal and adult outpatient clinic registries, prescription records and self-reported medication usage by the women. Site-level data synthesis (fixed effects and random effects) was conducted as well as individual-level analysis (fixed effects by site). RESULTS: Overall, 1915 newborns were included with 92 and 26 exposed to ACT (artemether-lumefantrine) and quinine, respectively. In Burkina Faso, Mozambique and Kenya at recruitment, the mean age (standard deviation) was 27.1 (6.6), 24.2 (6.2) and 25.7 (6.5) years, and the mean gestational age was 24.0 (6.2), 21.2 (5.7) and 17.9 (10.2) weeks, respectively. The LBW prevalence among newborns born to women exposed to ACT and quinine (QNN) during the first trimester was 10/92 (10.9%) and 7/26 (26.9%), respectively, compared to 9.5% (171/1797) among women unexposed to any anti-malarials during pregnancy. Compared to those unexposed to anti-malarials, ACT and QNN exposed women had the pooled LBW prevalence ratio (PR) of 1.13 (95% confidence interval (CI) 0.62-2.05, p-value 0.700) and 2.03 (95% CI 1.09-3.78, p-value 0.027), respectively. Compared to those unexposed to anti-malarials ACT and QNN-exposed women had the pooled SGA PR of 0.85 (95% CI 0.50-1.44, p-value 0.543) and 1.41 (95% CI 0.71-2.77, p-value 0.322), respectively. Whereas compared to ACT-exposed, the QNN-exposed had a PR of 2.14 (95% CI 0.78-5.89, p-value 0.142) for LBW and 8.60 (95% CI 1.29-57.6, p-value 0.027) for SGA. The level of between sites heterogeneity was moderate to high. CONCLUSION: ACT exposure during the first trimester was not associated with an increased occurrence of LBW or SGA. However, the data suggest a higher prevalence of LBW and SGA for children born to QNN-exposed pregnancies. The findings support the use of ACT (artemether-lumefantrine) for the treatment of uncomplicated malaria during the first trimester of pregnancy.

Fetal biometry assessment with Intergrowth 21st's and Salomon's equations in rural Burkina Faso.

BACKGROUND: Ultrasound scanning during the 2nd or the 3rd trimester of pregnancy for fetal size disturbances screening is heavily dependent of the choice of the reference chart. This study aimed to assess the agreement of Salomon and the Intergrowth 21st equations in evaluating fetal biometric measurements in a rural area of Burkina Faso, and to measure the effect of changing a reference chart. METHODS: Data collected in Nazoanga, Burkina Faso, between October 2010 and October 2012, during a clinical trial evaluating the safety and efficacy of several antimalarial treatments in pregnant women were analyzed. We included singleton pregnancies at 16-36 weeks gestation as determined by ultrasound measurements of fetal bi-parietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). Expected mean and standard deviation at a given gestational age was computed using equations from Salomon references and using Intergrowth 21st standard. Then, z-scores were calculated and used subsequently to compare Salomon references with Intergrowth 21st standards. RESULTS: The analysis included 276 singleton pregnancies. Agreement was poor except for HC: mean difference - 0.01, limits of agreement - 0.60 and 0.59. When AC was used as a surrogate of fetal size, switching from the reference of Salomon to the standards of Intergrowth 21st increased ten times the proportion of fetuses above the 90th percentile: 2.9 and 31.2%, respectively. Mean differences were larger in the third trimester than in the second trimester. However, agreement remained good for HC in both trimesters. Difference in the proportion of AC measurements above the 90th percentile using Salomon and Intergrowth 21st equations was greater in the second trimester (2.6 and 36.3%, respectively) than in the third trimester (3.5 and 19.8%, respectively). The greatest difference between the two charts was observed in the number of FL measurements classified as large in the second trimester (6.8 and 54.2%, using Salomon and Intergrowth 21st equations, respectively). CONCLUSION: The agreement between Intergrowth 21st and Salomon equations is poor apart from HC. This would imply different clinical decision regarding the management of the pregnancy.

A microplanning model to improve door-to-door health service delivery: the case of Seasonal Malaria Chemoprevention in Sub-Saharan African villages.

BACKGROUND: Malaria incidence has plateaued in Sub-Saharan Africa despite Seasonal Malaria Chemoprevention's (SMC) introduction. Community health workers (CHW) use a door-to-door delivery strategy to treat children with SMC drugs, but for SMC to be as effective as in clinical trials, coverage must be high over successive seasons. METHODS: We developed and used a microplanning model that utilizes population raster to estimate population size, generates optimal households visit itinerary, and quantifies SMC coverage based on CHWs' time investment for treatment and walking. CHWs' performance under current SMC deployment mode was assessed using CHWs' tracking data and compared to microplanning in villages with varying demographics and geographies. RESULTS: Estimates showed that microplanning significantly reduces CHWs' walking distance by 25%, increases the number of visited households by 36% (p < 0.001) and increases SMC coverage by 21% from 37.3% under current SMC deployment mode up to 58.3% under microplanning (p < 0.001). Optimal visit itinerary alone increased SMC coverage up to 100% in small villages whereas in larger or hard-to-reach villages, filling the gap additionally needed an optimization of the CHW ratio. CONCLUSION: We estimate that for a pair of CHWs, the daily optimal number of visited children (assuming 8.5mn spent per child) and walking distance should not exceed 45 (95% CI 27-62) and 5 km (95% CI 3.2-6.2) respectively. Our work contributes to extend SMC coverage by 21-63% and may have broader applicability for other community health programs.

Four Artemisinin-Based Treatments in African Pregnant Women with Malaria.

BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study.

BACKGROUND: The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant's health. METHODS: Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin-piperaquine (DHA-PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday. RESULTS: Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found. CONCLUSIONS: Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings. Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423.

The assessment of gestational age: a comparison of different methods from a malaria pregnancy cohort in sub-Saharan Africa.

BACKGROUND: Determining gestational age in resource-poor settings is challenging because of limited availability of ultrasound technology and late first presentation to antenatal clinic. Last menstrual period (LMP), symphysio-pubis fundal height (SFH) and Ballard Score (BS) at delivery are therefore often used. We assessed the accuracy of LMP, SFH, and BS to estimate gestational age at delivery and preterm birth compared to ultrasound (US) using a large dataset derived from a randomized controlled trial in pregnant malaria patients in four African countries. METHODS: Mean and median gestational age for US, LMP, SFH and BS were calculated for the entire study population and stratified by country. Correlation coefficients were calculated using Pearson's rho, and Bland Altman plots were used to calculate mean differences in findings with 95% limit of agreements. Sensitivity, specificity, positive predictive value and negative predictive value were calculated considering US as reference method to identify term and preterm babies. RESULTS: A total of 1630 women with P. falciparum infection and a gestational age > 24 weeks determined by ultrasound at enrolment were included in the analysis. The mean gestational age at delivery using US was 38.7 weeks (95%CI: 38.6-38.8), by LMP, 38.4 weeks (95%CI: 38.0-38.9), by SFH, 38.3 weeks (95%CI: 38.2-38.5), and by BS 38.0 weeks (95%CI: 37.9-38.1) (p < 0.001). Correlation between US and any of the other three methods was poor to moderate. Sensitivity and specificity to determine prematurity were 0.63 (95%CI 0.50-0.75) and 0.72 (95%CI, 0.66-0.76) for LMP, 0.80 (95%CI 0.74-0.85) and 0.74 (95%CI 0.72-0.76) for SFH and 0.42 (95%CI 0.35-0.49) and 0.77 (95%CI 0.74-0.79) for BS. CONCLUSIONS: In settings with limited access to ultrasound, and in women who had been treated with P. falciparum malaria, SFH may be the most useful antenatal tool to date a pregnancy when women present first in second and third trimester. The Ballard postnatal maturation assessment has a limited role and lacks precision. Improving ultrasound facilities and skills, and early attendance, together with the development of new technologies such as automated image analysis and new postnatal methods to assess gestational age, are essential for the study and management of preterm birth in low-income settings.